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Liu H , Cheng D , Weichel AK , Osipo C , Wing LK , Chen B , Louis TE , Jordan VC
Cooperative effect of gefitinib and fumitremorgin c on cell growth and chemosensitivity in estrogen receptor alpha negative fulvestrant-resistant MCF-7 cells
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The selective ER downregulator, fulvestrant, is currently approved as a second line endocrine therapy after onset of resistance to prior antiestrogen therapy in postmenopausal breast cancer patients. Resistance to antihormonal therapies is common and, therefore, we anticipate that fulvestrant-resistance will occur as well. The current study was undertaken to investigate the underlying molecular changes after fulvestrant-resistance and find new therapeutic targets and agents for fulvestrant-resistant breast cancer cells. We developed a unique fulvestrant-resistant cell line (MCF-7/F), derived from MCF-7 estrogen receptor alpha (ER alpha)positive human breast cancer cells, by culturing them in 1 mu M fulvestrant containing medium for - 18 months. MCF-7/F cells became irreversibly ER alpha negative as withdrawal of fulvestrant did not alter the ER alpha-negative phenotype, determined by real-time PCR, Western blot analysis, and ERE-luciferase transfection assays. MCF-7/F cells ! grew in a hormoneindependent manner. Interestingly, MCF-7/F cells overexpressed both epidermal growth factor receptor (EGFR) and breast cancer resistant protein (BCRP). Gefitinib, a specific EGFR tyrosine kinase inhibitor, preferentially inhibited the growth of MCF-7/F cells relative to MCF-7 cells by inhibiting both MAPK(44/42) and Akt phosphorylation. MCF-7/F cells became less sensitive to chemotherapeutic agents such as mitoxantrone. Moreover, furnitremorgin C, a specific BCRP inhibitor, si-nificantly increased the efficacy of mitoxantrone in MCF-7/F cells. Gefitinib increased the inhibitory effect of mitoxantrone on cell growth. Similarly, furnitremorgin C increased the inhibitory effect of gefitinib on cell growth, suggesting that there is a bidirectional crosstalk between EGFR and BCRP. More importantly, these results provide a molecular basis for using gefitinib, BCRP inhibitors, and chemotherapeutic agents as combination therapy approaches in fulvestrant-resistant b! reast cancer.